Gastrin-releasing peptide (GRP) receptors are present in pancreatic islets, though their regulation is unknown except for homologous desensitization. The modulation of binding of GRP to mouse pancreatic islets and INS-1 cells was studied. At 60 min (steady-state), total binding of [ 125 I-Tyr 15 ] GRP was 1 . 62 per cent of total radioactivity per 50 islets; non-speciยฎc binding ( presence of 1 mM unlabelled GRP(1-27)) was 0 . 05 to 0 . 61 per cent of total radioactivity. A preincubation with 1000 nM cholecystokinin (CCK 8 ) or with 1000 nM glucose-dependent insulinotropic peptide (GIP) augmented the number of GRP binding sites but not their anity. [ 125 I-Tyr 15 ]GRP binding to INS-1 cells was saturable (90 min) and speciยฎc with respect to compounds that are not chemically related to GRP (e.g. calcitonin gene-regulated peptide ร CGRP and atrial natriuretic peptide ร ANP). Displacement studies showed one binding site with a K d of 0 . 39 nM and a B max of 13 . 2 fmoles mg ร1 protein. When the cells were pretreated for 24 h with 10 nM GIP or CCK 8 , only GIP but not CCK 8 increased the B max of the GRP binding site. The anity (K d ) was not changed by either compound. This eect of GIP pretreatment was not aected by downregulating PKC by TPA ( phorbol ester; long-term pretreatment). These data indicate that: (1) speciยฎc binding sites for GRP are present in mouse pancreatic islets and INS-1 cells; (2) the GRP binding is upregulated by GIP in both islets and INS-1 cells and additionally by CCK 8 , albeit only in islets; and (3) PKC does not seem to be involved in the up-regulation process. Thus a positive interplay between both the incretins GIP and CCK 8 and the neurotransmitter GRP is obvious.